Thesis (MScAgric)--Stellenbosch University, 1978. / In title Greek letter 'alpha' is in subscript. / ENGLISH ABSTRACT: 1. Preliminary observations proved that an intramuscular injection of 62,5pg Cloprostenol terminates the oestrus cycle of ewes. Higher dosages (1251jg, 250pg and 500pg) caused a more abrupt termination of the cycle and more synchronised occurrence of oestrus. However, 125pg was only effective in terminating the oestrus cycle when injected between days 4 and 14. 2. In order to overcome this refractory period to Cloprostenol treatment, (days 15 through oestrus to day 4 of the oestrus cycle) ewes were treated with intravaginal progestogen sponges for 8 - 9 days and injected with Cloprostenol on the day of sponge withdrawal. A dosage of 31,251ig proved adequate, but conception rates were significantly lower at the first post treatment oestrus (mean 63,7%) as compared to the second post treatment oestrus (mean 81,9%). The change in the serum progesterone concentration following the cessation of treatment was not affected by the dosage of Cloprostenol (31,251g; 62,5pg and 125pg), but the position of the LH peak relative to the onset of oestrus varied markedly. The stage of the cycle when the intravaginal sponge treatment started had a significant affect on the interval between the cessation of treatment, the onset of oestrus and the LH peak. 3. The time of Cloprostenol administration relative to intravaginal sponge withdrawal (-48, -24 and 0h) showed no significant effect on either the oestrus response or the duration of oestrus. However, for the group receiving the prostaglandin injection at sponge withdrawal (Oh) the interval between cessation of treatment and oestrus showed a marked decrease as the onset of the progestogen treatment progressed from day 2 to day 17 of the oestrus cycle. The reproductive efficiencies of the three respective treatment groups did not differ significantly from each other, neither was there a significant difference between the reproductive performances at the first and the second post treatment oestrus. 4. An alternative method of bypassing the refractory period of the corpus luteum to prostaglandin is by giving two injections of prostaglandin 8 to 14 days apart. In this experiment different dosages (31,25pg; 62,5pg; 125pg and 250pg) of Cloprostenol were injected at a 10 day interval. Mn increase in the dosage was followed by a significant increase in the oestrus response (50,0%; 56,3%; 81,3% and 100,0% respectively). The higher dosages (250pg) of Cloprostenol cause more rapid and complete luteolysis as is reflected in the decrease in plasma progesterone concentration, while lower dosages (31,25pg and 62,5pg) often fail. 5. The reproductive efficiencies of ewes treated with the intravaginal progestogen sponge (MAP), an intravaginal progestogen sponge (MAP) followed by an injection of Cloprostenol (125pg), a double injection of 250pg Cloprostenol at a 9 day interval and a control groupwere compared. The oestrus response, the interval from cessation of treatment to the onset of oestrus and the duration of oestrus did not differ significantly for the respective groups. The mean conception rate of ewes treated with a double injection of Cloprostenol at a 9 day interval was significantly lower (36%) than that of the other groups (mean of 71,9%). G. In a 2 x 2 factorial experiment the reproductive efficiency of ewes treated with a double injection of prostaglandin at a 10 day interval and of a group of progestogen sponge (MAP) treated ewes were compared following insemination at observed oestrus and insemination at a predetermined time. The prostaglandin treated group was inseminated at 60 and 72 hours following the last injection of Cloprostenol and the sponge treated group at 48 and 60 hours following sponge withdrawal. Although the conception rates of the ewes were about 10% lower following fixed time A.I. as compared to A.I. at obs'arved oestrus, these differences were not significant. 7. The reproductive efficiencies of ewes treated with two injections of prostaglandin (Cloprostenol) administered at intervals of 9, 10 and 11 days, were compared. The conception rates of ewes in these treatment groups were 11,1%; 40,0% and 70,0% respectively and that of the control group 82,4%. These differences indicate the importance of injecting Cloprostenol at an interval of at least 11 days. / AFRIKAANSE OPSOMMING: 1. Voorlopige waarnemings bewys dat intramuskulere inspuiting van 62,5pg Cloprostenol die estrus siklus van ooie beeindig. Hoer dosisse (125pg, 2501jg en 500pg) veroorsaak 'n meer effektiewe en meer gesinkroniseerde estrus reaksie. Die gebruik van 124ig Cloprostenol is gevind om voldoende te wees om effektiewe luteoliese te veroorsaak vanaf dag 4 tot 14 van die estrus siklus. 2. Die sinkronisasie van die estrus periode met Cloprostenol is gedoen met 'n voorafbehandeling van intravaginale sponse, bevattende medroksie-progesteroon asetaat vir 8 - 9 dae, om die refraktoriese periode te oorbrug (dag 15 - 3). Die aanteeldoeltreffendheid van die verskillende behandelde groepe het geen noemenswaardige patroon gevolg nie, alhoewel die vrugbaarheid betekenisvol verskil het vir die eerste nabehandelings estrus (gemid. 63,7%) en die tweede (normals) na-behandelings estrus (gemid. 81,9%). Aangaande die serum progesteroon konsentrasies is gevind dat die tempo van .afname in progesteroon konsentrasie na begindiging van behandeling, nie betekenisvol beinvloed is deur die verskillende dosisse (31,2514; 62,5pg en 125pg) van prostaglandien nie— Heelwat variasie in die posisie van die LH piek t.o.v. die begin van estrus is gevind en dit was duidelik dat die stadium van die estrus siklus betekenisvolle effek op die interval tussen die beeindiging van behandeling en die voorkoms van die LH piek het. 3. Dit is gevind dat die tyd (-48, -24 en Oh) van Cloprostenol toediening relatief tot intravaginale spans onttrekking geen betekenisvolle effek op beide die estrus reaksie of die lengte van die estrus periode het nie. Alhoewel, vir die groep wat 'n prostaalandien inspuiting by spans onttrekking ontvang het (Oh), is 'n duidelike afname in die interval tussen die beeindiging van behandeling en estrus waargeneem soos die - stadium van progesteroon behandeling gewissel het van dag 2 tot dag 17 van die estrus siklus. Die aanteeldoeltreffendheid vir die onderskeie behandelings groepe het nie betekenisvol verskil van mekaar nie en oak was dear geen betekenisvoile verskil in die aanteeldoeltreffendheid by die eerste en tweede (normale) na-behandelings estrus nie. 4. 'n Alternatiewe metode am die refraktoriese periode van die corpus luteum tot prostaglandien te oorbrug, is deur die toediening van twee inspuitings prostaglandien 8 tot 14 dae uitmekaar. Verskillende dosisse (31,25pg; 62,5pg: 125pg en 250/4) Cloprostenol is gegee met 'n 10 dae interval tussen die inspuitings. Vermeerdering van die dosis is gevolg deur 'n betekenisvolle verhoging in die estrus reaksie (50,0%; 56,3%; 81,3% en 100,0% respektiewelik). Die hoer dosisse (2501jg) Cloprostenol veroorsaak meer vinnige en doeltreffende luteoliese terwyl die laer dosiese (31,25pg en 62,5pg) dikwels ondoeltreffend is. Die 250pg Cloprostenol groep het die vinnigste afname in die gemiddelde serum progesteroon konsentrasie getoon. 5. Die aanteeldoeltreffendheid tussen intravaginaleprogesteroon sponse (MAP) gevolg deur 'n inspuiting van Cloprostenol (125pg), 'n dubbele inspuiting Cloprostenol met 'n 9 dae interval en 'n kontrole groep is vergelyk. Die estrus reaksie, die interval vanaf beeindiging van behandelino tot begin van estrus en die lengte van die estrus periode het nie betekenisvol verskil vir die verskillende groepe nie. Die gemiddelde konsepsie syfer van ooie behandel met 'n dubbele inspuiting Cloprostenol met 'n 9 dae interval, was betekenisvol laer (36%) as die ender groepe (gemid. 71,9%). 6. In 'n 2 x 2 faktoriale eksperiment is vrugbaarheid, na inseminasie op waargeneemde estrus en inseminasie wat op 'n tydsbasis uitgevoer is, tussen dubbele inspuiting prostaglandien groep met 'n 10 dae interval en 'n intravaginale MAP) spons groep vergelyk. Die dubbel inspuiting groep is geinsemineer 60 en 72 uur na die laaste inspuiting en die spons groep is geinsemineer 48 en 60 uur na spons onttrekking. Alhoewel die konsepsie syfers van ooie ongeveer 10% leer was na inseminasie op 'n vasgestelde tyd teenoor inseminasie na waargeneemde estrus, was die verskil nie betekenisvol nie.

Prostaglandins (PG) play a major role in many endogenous processes including inflammation, labor, reproduction, and blood clotting. In the last two decades, these lipid signaling molecules have shown great potential as ocular hypotensive agents. Intraocular pressure (IOP) is a major risk factor in primary open-angled glaucoma (POAG), the second leading cause of blindness world-wide. Currently, prostaglandin F(2α) analogues are the most widely prescribed medications used to treat ocular hypertension. Studies have identified that almost all prostaglandin analogues exhibit anti-hypertensive effects in the eye, although they are not clinically available. Initial studies attributed the decrease in IOP observed to changes in hydraulic conductivity across the pressure-independent or uveoscleral pathway. More recent studies have shown that prostaglandin F(2α) analogues also lower IOP by affecting the pressure-dependent or trabecular pathway--the diseased tissue in POAG. Little is currently known about PG endogenous function, or the etiology of POAG. However, these studies suggest prostaglandin involvement in the maintenance of IOP in humans and identify the potential of PG analogues to treatment ocular hypertension. The research and findings presented in this dissertation address three specific aims designed to test the hypothesis that Endogenous prostaglandins, prostaglandin enzymes and prostaglandin receptors are involved in regulating conventional outflow facility. Specific aim 1 characterizes the distribution and activity of prostamide/prostaglandin F synthase (PM/PGFS) in the mouse and human eye using immunohistochemistry, western blot analysis and thin layer chromatography. Using techniques in biochemistry, molecular biology and physiology, specific aim 2, identifies the presence of the PG-EP₄ receptor within the outflow pathways, and the efficacy of a selective PG-EP₄ agonist, 3,7-dithiPGE₁, is also determined. Finally, specific aim 3 identifies PG-EP4 receptor coupling and downstream signaling using in vitro assays of transfected and primary cell lines to measure cAMP accumulation after treatment with a PG-EP₄ agonist. Collectively, these studies reveal the importance of PGE₂ synthesis and signaling to the conventional outflow pathway. They identify the PG-EP₄ receptor as a regulator of aqueous outflow and provide more specific therapeutic targets for the treatment of POAG.

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D.Sc. / Please refer to full text to view abstract

D.Phil. (Chemistry) / Please refer to full text to view abstract

I have investigated the effects o f both systemic and intracerebroventricular administration o f non-steroidal anti-inflammatory drugs (NSAIDs), o f varying therapeutic potency, on i) nociception during tail ischaemia and ii) hyperalgesia to a noxious thermal stimulus, evident during reperfusion of the receptive field on the tail, in conscious Sprague-Dawley rats. NSAIDs were found to attenuate the hyperalgesia evident during reperfiision o f the tail, whilst having no effect on the escape latency to a noxious ischaemic stimulus or on the tail flick latency in the absence of tail ischaemia. The intracerebroventricular doses required to attenuate reperfiision hyperalgesia were 2-3 orders o f magnitude less than those required by systemic administration for the same drugs. Using mechanical search stimuli, I located neurones in the dorsal horn of the spinal cord of rats with receptive fields in the tail. Neuronal responses to noxious and innocuous mechanical stimulation, as well as to noxious thermal stimulation before ischaemia and during reperfusion after ischaemia, were assessed. Of the population of neurones I examined, only a minority responded to thermal stimulation before ischaemia, and during reperfiision the neurones became more sensitive to mechanical stimuli, but not to noxious thermal stimuli. Furthermore, the neurones exhibited a decreased sensitivity to mechanical stimulation during ischaemia. Application of NSAIDs to the spinal cord did not alter the response properties of the neurones during receptive field ischaemia, but decreased receptive field size and reduced spontaneous and evoked activity during reperfusion of the tail. I have shown that the neurochemical mechanisms underlying nociception during ischaemia and reperfusion of the rat tail are different. While prostaglandins appear to pla] .0 role in mediating nociception during ischaemia, they are mediators of the hyperalgesia and neuronal hypersensitivity evident during receptive field reperfusion.

Prostaglandins (PGs) are medicinally interesting because of the wide variety of roles they play in the body. PGs are ubiquitous and can be found in the reproductive system, the nervous system, the cardiovascular system, and the immune system. Accordingly, PGs are an important therapeutic target for pharmaceutical companies, and an efficient synthesis is highly desirable. Past research indicates that an approach to prostaglandins via a chiral acetylenic ester or amide provides a promising method for control of C-15 geometry. This project seeks to validate a key stereospecific reduction of an enantiomerically pure cyclopentenone intermediate. This is in turn available from a chiral acetylenic ester or amide via a formal [3+2] cycloaddition step. Several methods have been investigated for asymmetric synthesis of the requisite chiral acetylenic acid derivative including asymmetric conjugate addition, CBS-oxazaborolidine reduction of a ketone, and the separation of diastereomers of a chiral amide. With the optically pure cyclopentenone in hand, we will investigate hydroxyl directed conjugate reduction of the cyclopentenone double bond.